Bismuth salts of a monoalkyl polycarboxylate and process of making them



Patented Mar. 8, 1938 UNlTED STATES PATENT OFFICE BISMUTH SALTS OF AMONOALKYL POLY- CARBOXYLATE AND PROCESS OF MAKING THEM No Drawing.Application September 30, 1936,

Serial No. 103,457

11 Claims.

This invention relates to bismuth salts of acid esters of polycarboxylicacids with aliphatic alcohols of at least ten carbon atoms.

This case is a continuation in part of my cpending application SerialNo. 726,108, filed May This invention has as an object the preparationof bismuth salts of acid esters of aliphatic alcohols withpolycarboxylic acids. A further object is the preparation of bismuthsalts of acid esters of phthalic acid. A still further object is thepreparation of oil-soluble bismuth alkyl polycarboxylates. A stillfurther object is the preparation of compositions useful in combatingsyphilis and other spirochetal diseases. A still further object is theprovision of processes whereby these bismuth salts may be prepared.Other objects will appear hereinafter.

These objects are accomplished by the following invention wherein thereare prepared bismuth salts of acid esters of polycarboxylic acids withaliphatic alcohols of at least ten carbon atoms, for example, thebismuth salt of monododecyl phthalate.

' The neutral salts of bismuth with polycarboxylic acids partiallyesterified with monohydric aliphatic alcohols of at least ten carbonatoms are preferably prepared by reacting in aqueous oraqueous-alcoholic solution a salt of the acid ester, for example thesodium salt, with an aqueous solution of a bismuth salt preferablycontaining a water soluble polyhydric alcohol such as mannitol. Thebismuth salt of the acid ester precipitates and may be separated fromthe supernatant 3;, liquid by filtration. If desired, the compound soprepared may be further purified by dissolving, for example in anaromatic hydrocarbon, removing the small amount of dissolved water bymeans of a dehydrating agent, such as anhydrous sodium sulfate, andfiltering off the insoluble residue. The bismuth salt of thepolycarboxylic acid ester may, if desired, be used in solution or may beisolated, for example, by evaporation of the solvent.

In preparing the bismuth salt of the alkyl polycarboxylates, bismuthoxide or hydroxide is reacted with the acid ester or a bismuth salt isreacted with a salt of the acid ester. Water soluble bismuth salts mayin general be employed. For so purity of product and convenience inoperation the bismuth salt such as the nitrate is preferably dissolvedin an aqueous solution of a polyhydric alcohol such as mannitol.

Having outlined the general principle of the invention above, thefollowing applications theret to to certain specific instances areincluded for purpose of illustration and not in limitation.

EXAMPLE I Bismuth trz's (monododecyZ-phthalate) Sixty and two tenthsgrams (0.15 mol.) of dodecyl acid phthalate was dissolved in 120 gramsof alcohol and neutralized with a 17% caustic soda solution usingphenol-phthalein as the indicator. A solution of bismuth nitrate wasmade as follows: Twenty-four and two tenths grams (0.05 mol.) ofhydrated bismuth nitrate and 9 grams of mannitol were pulverizedtogether and then dissolved in 200 cc. of water. The bismuth nitratesolution was poured slowly into the sodium dodecyl phthalate solution. Asticky viscous oily layer settled out. After stirring for about an hourand allowing to settle, the clear supernatant liquid was decanted. Thewet oily layer which weighed 76 grams was dissolved in 60 grams ofbenzene and dried with anhydrous sodium sulfate. After filtering off thesodium sulfate the clear, pale-yellow solution weighed 110 grams. tanalyzed 47.3% total solids and'7.9% of bismuth metal which correspondsto 16.7% bismuth calculated on the solids. The calculated bismuthcontent of bismuth tris (mcnododecyl phthalate) is 17.3%. The benzenewas removed from a portion of the filtered solution by evaporating toconstant weight under a water. pump vacuum on a water bath. The residuewas a pale-yellow, viscous, sticky liquid. Five tenths grams of thismaterial was readily dissolved in 5 grams of olive oil. The benzenesolution showed no sign of separation after storing 7 months.

In preparing the acid ester, the reaction is, in general, carried out byheating the alcohol and the anhydride for a period of at least minutes.A wide range of temperature may be used but a temperature range ofl20-l50 C. is preferred. This treatment is sufiicient to cause theanhydride to react with the hydroxyl group of the alcohol in arelatively short time. The course of the esterification may readily befollowed by titration of samples with standard alkali. Thus, inpreparing monododecyl phthalate, the theoretical acid number is obtainedafter heating at 140 C. for one-half hour or at 120 C. for one hour.

The phthalic acid ester is then neutralized in aqueous alcohol solutionwith sodium or potassium hydroxide or carbonate to obtain the solutionof the neutral alkali metal salt which in turn is treated with a watersoluble salt of bismuth to 7 obtain by double decomposition the saltdesired.

In preparing the acid ester in general, any alcohol of at least tencarbon atoms may be em-.

ployed including decyl, dodecyl, tetradecyl, cetyl, octadecyl,9,10-octadecenyl, eicosyl, ricinoleyl, eleostearyl, abietyl,tetradecahydroanthracenyl, myricyl, alpha and beta .decahydronaphthyl,undecyl, undecylenyl and naphthenyl alcohols, particularly naphthenylalcohols -of tento. thirteen carbon atoms. Mixtures of alcohols may beemployed. While primary fatty alcohols such as are obtained by thecarboxyl hydrogenation of vegetable oils, for example, coconut oil orcotton seedoil as disclosed in copending application of W. A. Lazier,Serial No. 445,224,'filed 'April 17,

1930, or in W. A. Lazier US. Patent 1,839,974'are preferred, it is to beunderstood that other alco-" hols may be used, for example, the alcoholsobtainedby the hydrogenation of animal oils such as sperm oil, thealcohols obtained by hydrating olefines produced by the cracking, ofparaffin wax or the higher alcohols produced in the catalytichydrogenation of carbon monoxide. These latter include a large number ofhigh molecular weight branched chain alcohols, some of which are usedin'the processor the present invention,

e. g., those of at least ten carbons.

In preparing theacid ester of the polycarboxylic acid, it .isparticularly desirable, because of convenience of operation, etc., touse the anhydride of the polycarboxylic acid where'this is possible.This allows a more ready formation of acid esters and minimizes. theformation'of neutral, esters. The term polycarboxylic .acid in,

the claims is'therefore to be understood as including the anhydridesthereof. It is, however, a

possible to makethe compounds by processes in which the acid is itselfused. Similarly, the acid esters maybe made by the use of the acidchloride with an excess .of the particular alcohol or may even be madefrom the neutral ester and alcohol and anester interchange catalyst. Thephthalic anhydride may be replacedby other .carboxylic acids oranhydrides suchas succinic, malic, maleic, fumaric, adipic, citric,camphoric, hexahydrophthalic, trimesic and quinolinic.- Thosedicarboxylic acids are preferred, in which the carboxyl groups areattached to adjacent carbon atoms, such as phthalic acid, succinic acidor maleic acid. These acids as a. class possess two unique advantagesover other 'dibasic acids.

I First, by virtue of their ability to form cyclicanhydrides they lendthemselves readily to the;

preferred process 'of producing the monoesters,

namely by heating the anhydrides with substantially equivalentquantities of the alcohols This reaction forms the monoester with nosubstantial lay-products, whereas the direct esterification of adicarboxylic acidwhich does not readily form an anhydride results in a.mixture of monoester with the di-ester as well as unchanged acid.

The presence of these impurities isa source of considerable difficultyin obtaining pharmaceutically valuable products, A second advantage of1,2-dicarboxylic acids .is the uniquely superior organic solubilityofthe resulting ester-salts.

While Ido not wish tobe limited by theory, it is my belief that thesepreferred ester-salts exist 1 I as chelater-compounds. 2 In thecase ofoxy-bis muth dodecyl phathalate, the chelate nature of the compound isrepresented by the structure CQO- CuHu e oino o where the dotted linerepresents a coordination valency between the metal and the ester group,and completes acyclic structure. By virtue'of this cyclic structure, theproduct loses its salt like character as'is evidenced'by lowmeltingpointand high .organicsolubility. The further the carboxyl' andthe ester groups are removed from one another, the more diflicultbecomes chelate ring-formation. Even the 1,2-di'carboxylic acidestersnecessitate the rather unusual '7- membered ring in order to formchelates, and the dicarboxylic acids in which the carboxyl groups areseparated by more than two carbon atoms form monoesters with practicallyno'tendency to chelate with metals. 7 v Basic bismuth compoundsofmonoalkylphthalatesmay alsobe prepared as above indicated,

e. g., by heating bismuth oxide with monododecyl phthalate on a waterbath; 0xy-bismuthdodecyl phthalate of 37.5%, bismuth content, and

oxy-bismuth-octadecyl phthalate of 32.6%, bis

muth content, may thus be prepared." a V The compounds of the typeherein disclosed are soluble in many organic solvents, for example,

toluene. They offer therefore an advantageous method of incorporatingbismuth with organic materials.

Bismuth compounds or alkyl phthalates or at least ten carbon atoms havebeen found to be useful for pharmaceutical purposes and particularly inthe treatment of spirochetal infections, for example, syphilis. Theirlow toxicity and high'therapeutic effect combined with'their solubilityin oils,for examplefolive oil renders them particularly suitable forthis purpose. ubility is of paramount importance in applying thesetherapeutics by injection. The compounds of this invention are uniquelyvaluable in this respect. V V

The above description and examples are intended to be illustrative only.Any'modiflcation of or variation therefrom whichconforms to the spiritof the invention is intended to be included 7 within the scoperoftheclaims;

i V l. Bismuth tris (monododecyl phthalate) of a dicarboxylic acid, thealkyl group containing from ten'to thirty-one carbon atoms and thecarboxyls of the acid being on adjacent carbon atoms.

V '7. A bismuth salt of an acid ester of a poly- 'carboxylic acid withan alcohol containing from ten-'tothirty-one carbonatoms.

ethyl acetate, butyl acetate, butyl alcohol, and

8. In a process of preparing bismuth salts of acid esters ofpolycarboxylic acids the step which comprises reacting a solution ofbismuth nitrate in aqueous mannitol with an aqueous alcoholic solutionof sodium dodecyl phthalate.

9. In a process of preparing bismuth salts of acid esters ofpolycarboxylic acids the step which comprises reacting an aqueoussolution of bismuth nitrate containing mannitol with an aqueousalcoholic solution of a sodium salt of an acid ester of phthalic acidwith an aliphatic alcohol containing from ten to thirty-one carbonatoms.

10. In a process of preparing bismuth salts of acid esters ofpolycarboxylic acids the step which comprises reacting an aqueoussolution of bismuth nitrate containing mannitol with an equeousalcoholic solution of an alkali metal salt of an acid ester of apolycarboxylic acid with an aliphatic alcohol containing from ten tothirty-one carbon atoms.

11. In a process of preparing bismuth salts of acid esters ofpolycarboxylic acids the step which comprisesreacting bismuth ion inaqueous solution with an aqueous solution of a salt of an acid ester ofa polycarboxylic acid with an alcohol containing from ten to thirty-onecarbon atoms.

PAUL L. SALZBERG.

CERTIFICATE OF CORRECTION. 7 Patent No. 2,11o;u7 March 19 I PAUL Ii.SALZBERG. It is hereby, certified that error appears in the printedspecification of the above numbered patent requiring correction asfollows: Page 2, first column, line 75, for "chelater" read chelated;and second column, line 1, for

I "phathalate" read phthalate; line .60, claim 1 for "monoalky" readmonoalkyl page 5, second column, line}, claim 10, for "equeous" readaqueous; and that the said'Letters Patent should be'read with thesecorrections therein that the same may conform to the record of the casein the Patent Office,

Signed and sealed this 26th day of April, A. D. 19 8.

A 'Henry Van Arsdale, (Seal) Acting Commissioner of Patents.

